title: Recognition of the four Watson-Crick base pairs in the DNA minor groove by synthetic ligands.
abstract: The design of synthetic ligands that read the information stored in the DNA double helix has been a long-standing goal at the interface of chemistry and biology. Cell-permeable small molecules that target predetermined DNA sequences offer a potential approach for the regulation of gene expression. Oligodeoxynucleotides that recognize the major groove of double-helical DNA via triple-helix formation bind to a broad range of sequences with high affinity and specificity. Although oligonucleotides and their analogues have been shown to interfere with gene expression, the triple-helix approach is limited to recognition of purines and suffers from poor cellular uptake. The subsequent development of pairing rules for minor-groove binding polyamides containing pyrrole (Py) and imidazole (Im) amino acids offers a second code to control sequence specificity. An Im/Py pair distinguishes G x C from C x G and both of these from A x T/T x A base pairs. A Py/Py pair specifies A,T from G,C but does not distinguish AT from T x A. To break this degeneracy, we have added a new aromatic amino acid, 3-hydroxypyrrole (Hp), to the repertoire to test for pairings that discriminate A x T from T x A. We find that replacement of a single hydrogen atom with a hydroxy group in a Hp/Py pairing regulates affinity and specificity by an order of magnitude. By incorporation of this third amino acid, hydroxypyrrole-imidazole-pyrrole polyamides form four ring-pairings (Im/Py, Py/Im, Hp/Py and Py/Hp) which distinguish all four Watson-Crick base pairs in the minor groove of DNA.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena 91125, USA.
authors.forename: S
authors.initials: S
authors.lastname: White
authors.forename: J W
authors.initials: JW
authors.lastname: Szewczyk
authors.forename: J M
authors.initials: JM
authors.lastname: Turner
authors.forename: E E
authors.initials: EE
authors.lastname: Baird
authors.forename: P B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D001482:Base Composition; D004247:DNA / Q000378:metabolism*; D018983:DNA Footprinting; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D009757:Nylons / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D007093:Imidazoles; D008024:Ligands; D009757:Nylons; D011758:Pyrroles; C029899:imidazole; D004247:DNA